Two human monoclonal antibodies that react with membrane antigens associated with human melanoma have been produced in our laboratory. The chemical nature of the antigens was identified as the gangliosides GD2 and GM2, respectively. After laboratory and experimental animal studies of these antibodies, we recently initiated a human therapy trial. Eight patients with subcutaneous or intradermal metastatic melanoma received intra-tumor injections of antibody to GD2. Remarkable regression was observed in some of these patients, without noticeable side effects. To the best of our knowledge, we are the only group successfully producing human monoclonal antibodies to tumor antigens for use in clinical therapy trials. In this application, we will continue the study of intra-tumor injection of human monoclonal antibody, in order to define its anti-tumor effect in cancer patients. The study will examine a new treatment of cutaneous metastatic melanoma as well. Systemic injection of antibody for the treatment of hematogenous and lymphatic metastases will be performed when large-scale production of human monoclonal antibodies is accomplished as proposed in this application. The other arm of this proposal includes the generation of three additional antibodies to melanoma-associated antigens that have been identified and characterized in our laboratory. Preparation of several human monoclonal antibodies, each having a different specificity, is clinically important for two reasons: (1) antigenic expression on tumor cells in heterogeneous, and (2) a single type of surface antigen may not be sufficient for targeting by human monoclonal antibodies for immune cytolysis. We will investigate the potential of individual human monoclonal antibodies as well as a combination of multiple types of human monoclonal antibodies for the treatment of human cancer.